20(S) camptothecin glycoconjugates

Abstract

The present invention relates to glycoconjugates of 20(S)-camptothecin, in which a 3-O-methylated beta-L-fucose unit is linked to the 20-hydroxyl group of a camptothecin derivative via a thiourea-modified peptide spacer. The invention furthermore relates to processes for the preparation of the compounds according to the invention and to their use as medicaments, in particular in connection with oncoses.

What is claimed is:  
     
       1. A camptothecin glycoconjugate of formula (I)                    
       in which 
       R 1  represents a β- or γ-branching non-polar amino acid side chain; and  
       R 2  represents a basic amino acid side chain;  
       and their salts, stereoisomers and stereoisomer mixtures.  
     
     
       2. The compound of formula (I) according to  claim 1 , where 
       R 1  is a branched alkyl radical having up to 4 carbon atoms; and  
       R 2  is a radical of the formula —(CH 2 ) n —R 3 , where                    
       n is a number 1 to 4;  
       and their salts, stereoisomers and stereoisomer mixtures. 
     
     
       3. The compound of the formula (I) according to  claim 1 , where 
       R 1  is a branched alkyl radical of formula                    
       R 2  is a radical of the formula  
       
         
           —(CH 2 ) 2 —NH 2 , —(CH 2 ) 3 —NH 2 , —(CH 2 ) 4 —NH 2 ,  
         
         
           
           
               
               
           
         
       
        and their salts, stereoisomers and stereoisomer mixtures.  
     
     
       4. A process for the preparation of a glycoconjugate of formula (I)                    
       in which 
       R 1  represents a β- or γ-branching non-polar amino acid side chain; and  
       R 2  represents a basic amino acid side chain,  
       or of their salts, wherein the isothiocyanate of the formula (II)                    
        is reacted with the peptidyl-camptothecin, optionally bearing a protective group in the side chain, of the formula (III)                    
        in which  
       R 1  has the abovementioned meaning and  
       R 2′  has the meaning of the abovementioned basic radical R 2 , which moreover can carry a protective group on the basic group to give the glycoconjugate of the formula (IV)                    
        in which  
       R 1  and R 2′  have the meanings indicated above,  
       wherein the side chain amino protective group which may be present is optionally removed and the compound obtained is optionally converted into the desired salt.  
     
     
       5. A process for the preparation of compounds of the general formula (I) or of their salts, characterized in that the isothiocyanate of formula (II)                    
       is reacted with an optionally protected terminal basic amino acid of the formula (V)                    
       in which R 2′  represents a basic amino acid side chain whose basic group can be protected, 
       to give an amino acid conjugate of the formula (VI)                    
        in which R 2′  has the meaning indicated above,  
       this is then reacted with amino acid conjugates of the formula (VII)                    
        in which R 1  has the meaning indicated in  claim 1 ,  
       wherein the side chain protective group is optionally removed and the compounds are optionally converted into a suitable salt.  
     
     
       6. The compound 20(S)-20-O-{N α -[O-(3-O-methyl-β-L-fucopyranosyl)-4-hydroxy-phenylamino-thiocarbonyl]-L-lysyl-L-valyl}-camptothecin of the formula                    
       and its salts. 
     
     
       7. The compound 20(S)-20-O-{N α -[O-(3-O-methyl-β-L-fucopyranosyl)-4-hydroxy-phenylamino-thiocarbonyl]-L-histidyl-L-valyl}-camptothecin of the formula                    
       and its salts. 
     
     
       8. A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       9. A method for the treatment of oncoses, comprising administering to a mammal in need thereof an effective amount of a compound according to  claim 1 . 
     
     
       10. The method of  claim 9 , wherein said mammal is a human. 
     
     
       11. A method of inhibiting tumor growth in a mammal, comprising administering an effective amount of a compound according to  claim 1  to said mammal. 
     
     
       12. The method of  claim 11 , wherein said mammal is a human.